Lirafugratinib (Lyrfigtu)

Cholangiocarcinoma is a malignancy of the biliary epithelium classified by anatomic site as intrahepatic, perihilar, or distal, and biliary tract cancer accounts for less than 1% of all cancers worldwide. The American Cancer Society estimates that about 8,000 people in the United States are diagnosed with bile duct cancer each year. In the Surveillance, Epidemiology, and End Results program, the incidence of intrahepatic cholangiocarcinoma increased 148.8% from 2001 to 2017, from 0.80 to 1.99 per 100 000 person-years. FGFR2 fusions or rearrangements are reported in 10% to 16% of intrahepatic cholangiocarcinomas; central prescreening for FIGHT-202 identified them in 107 of 1,206 participants (9%), and a genomic profiling dataset identified FGFR2 rearrangements in 9.2% of 6,802 cholangiocarcinoma samples. Only part of the incident population reaches later-line therapy: 46% of 413 participants in a United States commercial-claims cohort with advanced biliary tract cancer received second-line treatment.

Five-year relative survival for liver and intrahepatic bile duct cancer is 37.4% for localized, 13.4% for regional, and 3.6% for distant disease. In first-line advanced disease, median overall survival was 12.9 months with durvalumab plus gemcitabine and cisplatin in the TOPAZ-1 three-year update and 12.7 months with pembrolizumab plus gemcitabine and cisplatin in KEYNOTE-966. After first-line progression, ABC-06 reported median overall survival of 6.2 months with FOLFOX plus active symptom control and 5.3 months with active symptom control alone, with an objective response in four of 81 participants (5%) receiving FOLFOX. FGFR genetic aberrations were associated with longer overall survival in an institutional series (37 versus 20 months).

The approved FGFR inhibitors pemigatinib and futibatinib produced objective response rates of 37.0% and 42% in their pivotal single-arm trials, with median progression-free survival of 7.0 and 9.0 months. Their labels report hyperphosphatemia from laboratory values in 93% and 88% of participants, and 49 of 82 participants (60%) had one or more secondary FGFR2 kinase domain mutations at acquired resistance to an FGFR inhibitor. The United States approval of infigratinib was withdrawn in 2024.

In the ABC-06 quality-of-life analysis, the EQ-5D utility value in the active symptom control arm fell from 0.75 at baseline to 0.62 at month 4. In a United States commercially insured cohort with advanced biliary tract cancer, mean all-cause costs were $18,274 per patient per month overall and $22,617 per patient per month during second-line therapy. The Canadian drug agency estimated that testing costs $38,000 to identify a single patient eligible for pemigatinib.